What is Legionnaires' disease?

Causes and Symptoms

Legionnaires’ disease, or legionellosis, is an acute bacterial pneumonia that was unknown prior to 1976. In July and August of that year, an outbreak of pneumonia occurred among persons who had either attended an American Legion convention in Philadelphia or had been in the vicinity of the Bellevue-Stratford Hotel in the downtown area. The likely source of the epidemic was a contaminated air-conditioning unit in the hotel. Though speculation among the media and general public suggested all sorts of causes for the epidemic, the specific etiological agent was isolated by January 1977. It turned out to be a somewhat common bacterium, which was subsequently given the genus and species names Legionella pneumophila; the genus name reflected the first known victims, while the species name meant “lung-loving.”

Within several years, additional strains of Legionella
bacteria were isolated from patients suffering from bacterial pneumonia. Through 2013, more than fifty species had been identified, of which slightly fewer than half have been associated with human disease. Most cases of Legionnaires’ disease have been linked to infection by L. pneumophila or, to a lesser degree, L. micdadei.

Genetic evidence confirmed that Legionella was indeed a newly isolated bacterium. Several factors contributed to its previous invisibility. First, Legionnaires’ disease is similar in its characteristics to other forms of nonbacterial pneumonia, such as that caused by viruses. Since no bacteria were readily isolated, there was no immediate reason to suspect a bacterium as the infectious agent. The second reason related to the initial difficulty of growing Legionella bacteria in the laboratory. Aspirates from pneumonia victims were inoculated onto routine laboratory media; most common bacteria grow quite readily on such media. No growth was observed, however, in the case of Legionella. Many nutrient supplements were tried. Legionella bacteria grew only on media that were supplemented with iron and the amino acid cysteine. Since the early 1980s, the medium of choice has been agar containing buffered charcoal yeast extract (BCYE). Nutrients such as amino acids, vitamins, and iron are included in the medium while the charcoal removes potentially toxic materials.

Legionellosis actually constitutes two separate clinical entities: Legionnaires’ disease and Pontiac fever. Legionnaires’ disease is potentially the more serious of the two. The victim is initially infected through a respiratory route. In general, the source of the infection is an aerosol generated by contaminated water supplies such as those found in the cooling units of building air-conditioning systems. Rarely, if at all, does the disease pass from person to person. Most infections are unapparent, with either mild disease or none at all. The estimate is that less than 5 percent of exposed individuals actually contract Legionnaires’ disease. Certain factors seem to increase the chances that the infection will progress toward pneumonia. Often, the lungs of the victim have suffered from previous trauma, such as that caused by emphysema or smoking. The person is generally, though not always, middle-aged or older. These observations suggest that, in most instances, the person’s immune system is quite capable of handling the infection.

The disease begins with a dry cough, muscle aches, and rising fever—symptoms that resemble the flu. The person may also suffer from vomiting and diarrhea. In serious cases, the disease becomes progressively more severe over the next three to six days. The alveoli, or air sacs, of the lung become necrotized, increasing the difficulty in breathing. Small abscesses may also form in the lungs, as phagocytes infiltrate the area. The mortality rate has ranged from 15 to 60 percent in various outbreaks, although with early treatment, these numbers can be significantly lowered. Patients with other underlying lung problems, or who may be immunosuppressed, are at particular risk.

Pontiac fever is a much less serious form of disease. Named for the Michigan city in which a 1968 outbreak occurred in the Public Health Department building, the disease is self-limiting, nonpneumonic, and not life-threatening. Pontiac fever also seems to follow the inhalation of the etiological agent. Though the attack rate in exposed individuals appears to approach 100 percent, there is no infiltration of lung tissue and no abscess formation. A febrile period occurs one to two days following infection, with the individual progressing to recovery after several days. The difference between the two forms of disease remains obscure. There appears to be no obvious difference between the organisms associated with the two diseases, though strains associated with Pontiac fever may not replicate as readily inside human cells.

The mechanism by which infection by Legionella bacteria results in pneumonia is not altogether clear. Research into this area has centered on forms of virulence factors produced by the organism and their relationships to disease. Following their infiltration into the lung, Legionella bacteria are phagocytized by alveolar macrophages or other leukocytes (white blood cells). Unlike other ingested microbes, however, Legionella bacteria often survive the process and begin a process of intracellular replication. In this intracellular state, Legionella bacteria are shielded from many of the host’s immune defenses.

Certain questions lend themselves to understanding this approach in elucidating the mechanisms of Legionnaires’ disease. First, are intracellular survival and multiplication necessary factors in the development of the disease? Second, if these factors are indeed relevant, exactly how does the organism manage to evade the killing mechanisms that exist inside the cell?

The first question has been dealt with by various animal studies. Guinea pigs were exposed to a Legionella aerosol, and lung aspirates were prepared after forty-eight hours. Large numbers of viable organisms were found inside alveolar macrophages. Few live Legionella bacteria, however, were observed outside cells. In addition, mutant Legionella bacteria that were incapable of intracellular growth showed reduced virulence in guinea pigs. Therefore, initial intracellular infection and multiplication does appear to be necessary to initiate the disease process.

The mechanism of intracellular survival is less clear. Macrophages are phagocytes that have a wide variety of means for killing ingested microorganisms. These mechanisms range from the production of reactive oxygen molecules to the synthesis of oxidizing agents such as peroxides. In addition, after a foreign microbe has been phagocytized within the membrane-bound vessel called a phagosome, a cell organelle, the lysosome, will fuse with the phagosome. Contained within the lysosome are large numbers of digestive enzymes that proceed to digest the target. Under normal circumstances, foreign microbes are ingested and digested, eliminating the threat of infection.

Somehow, Legionella bacteria evade these defense mechanisms. Different strains of Legionella bacteria appear to have evolved a variety of mechanisms for survival. In particular, there are two types of molecules, a phosphatase and a cytotoxin, whose presence is correlated with intracellular survival. Both appear to act by preventing the phagocytes from producing potentially lethal oxidation molecules such as hydrogen peroxide.

Another virulence factor that appears to be important for infectivity is a surface protein known as the macrophage infectivity potentiator, or MIP. The MIP proteins are apparently unique to Legionella bacteria; mutants that lack the MIP gene are significantly less virulent than wild-type strains. The MIP protein appears to be necessary for the internalization of Legionella bacteria by the macrophage, and for survival against the array of bacteriocidal activities.

A variety of other mechanisms may also exist that allow Legionella bacteria to escape the killing mechanisms of the macrophage. For example, in addition to the phosphatase, which removes phosphate molecules from host proteins or lipids, Legionella bacteria also produce protein kinases, which can add phosphate molecules to host cell proteins. In this manner, Legionella bacteria can potentially regulate the metabolism of the cells in which they find themselves by adding or subtracting phosphates from various sites or metabolic pathways.

Though a precise sequence of events that leads to the development of Legionnaires’ disease remains to be worked out, certain steps appear to be necessary. Following the inhalation of a Legionella aerosol, probably from a contaminated water source, the organism lodges in the alveoli of the lung. Resident macrophages phagocytize the microbe, resulting in its internalization. Through a variety of virulence factors, Legionella survives, and multiplies within the macrophage. Death of the host cells along with the concomitant infiltration of other white cells results in the inflammation and lung damage recognized as Legionnaires’ disease.

Treatment and Therapy

Despite the hysteria associated with the Philadelphia outbreak of Legionnaires’ disease and the difficulty associated with the initial isolation of the etiological agent, there is nothing particularly unusual about the organism. The Legionella bacterium is a small, thin microbe some two to ten micrometers in length, about the size of most average bacteria. Because of its characteristic staining pattern, it is classified as a gram-negative organism. This results from the molecular nature of its cell wall, which has a high lipopolysaccharide (LPS) content.

Since legionellosis can resemble other forms of pneumonia, improper diagnosis can be a problem. Though the prognosis of the disease is generally favorable with early intervention, improper or delayed treatment can prove fatal. In general, legionellosis is suspected in a patient with a progressive pneumonia for which other organisms do not appear to be a factor.

Legionnaires’ disease pneumonia may be diagnosed microbiologically in a number of ways. The simplest, most rapid, and least costly test is the urinary antigen. The test is available only for L. pneumophila serogroup 1, but this organism is responsible for the majority of pneumonia cases. The antigen is detectable in the urine three days after symptoms begin and persists for several weeks. Expectorated sputum or secretions obtained through bronchoscopy may be stained and cultured. A special stain to visualize the bacteria through the microscope, called direct fluorescent antibody (DFA), is very specific but not very sensitive, because it requires large numbers of bacteria to be positive and such number are usually present only in the most severe cases. The definitive diagnostic method is culture using BCYE media. The bacteria grow slowly and colonies become visible only after three to five days of incubation. Lastly, blood (sera) may be collected as acute and convalescent specimens. A fourfold rise in the antibody titer is considered diagnostic. A single specimen of high titer (1:128 dilution or higher) is considered presumptive, but not definitive, evidence of infection. In the case of Pontiac fever, serologic testing is the usual method for diagnosis.

There are several aspects of the clinical significance of the gram-negative character of the organism, one of which is that this type of bacteria responds poorly to penicillin or penicillin derivatives. This serves to limit the type of antimicrobial therapy available for treatment of severe cases of legionellosis. Other antibiotics exist, of course, that exhibit antibacterial characteristics similar to those of penicillin—for example, the cephalosporins. And, indeed, penicillin derivatives have been used to treat at least some types of gram-negative infections. Legionellosis patients did not respond well, however, to treatment with any of these agents. It was subsequently found that the basis for the resistance by Legionella bacteria to these antibiotics lay in a type of extracellular enzyme produced by these bacteria—a beta-lactamase.

The lack of pharmacologic activity associated with the penicillins, the cephalosporins, and certain other antibiotics is thus easy to explain. The activity of these antibiotics is associated with the presence of a structure in the molecule called a beta-lactam ring. The beta-lactamase produced by the Legionella bacterium causes a break in the ring, rendering the antibiotic harmless to the microbe, and thus useless as a form of treatment. Such resistance has become increasingly common among bacteria, since the genes encoding the beta-lactamase are passed from organism to organism.

Fortunately, other antibiotics did prove to be useful in the treatment of legionellosis. To a certain extent, the determination of the antibiotics of choice was fortuitous. During the Philadelphia outbreak, the nature of the illness was unknown. The primary assumption was that an infectious agent was at fault, but determination of the nature of that agent lay months beyond the extent of the epidemic. Therefore, as would be true in the treatment of any illness of unknown origin, various treatments were carried out. Two antibiotics in particular proved to be useful: erythromycin and rifampin. Erythromycin, which specifically inhibits bacterial protein synthesis, has continued to be useful. Though long-term use can result in liver damage and some individuals are hypersensitive to the drug, the intravenous administration of erythromycin remains the treatment of choice for legionellosis. Rifampin is used on occasion in association with other methods of treatment, but the high frequency of bacterial resistance to the drug precludes its use as a treatment of first choice.

Since the virulent properties of the Legionella bacterium depend on its intracellular presence in the macrophage, those antimicrobial agents that exhibit intracellular penetration would be expected to be most effective. Erythromycin fits this requirement, as do a number of other antibiotics. Newer antibiotics with intracellular activity have replaced erythromycin and rifampin as first choices for treatment of Legionnaires’ disease pneumonia. Azithromycin, a macrolide antibiotic similar to erythromycin, yields higher intracellular levels than erythromycin and has proven to be more effective. Alternative monotherapy can be employed using one of the new respiratory fluoroquinolones such as levofloxacin or moxifloxacin. The quinolones are used for those who have undergone transplantation, as they do not interfere with the immunosuppressive drugs used in these patients.

Other aspects of treatment center on maintaining the comfort of the individual. This may include the use of analgesics for relief of pain. Pontiac fever is a self-limiting disease and requires only such symptomatic therapy.

Prevention of the disease is obviously preferable to dealing with the sequelae of infection. Epidemiological studies have demonstrated that the Legionella bacterium is a common soil organism that is often found in bodies of water contaminated by soil. The organism has been found in lakes and pond water, and it can survive for long periods in unchlorinated tap water. In fact, contaminated water appears to have been the source of infection for most outbreaks of the illness. Problems have often been associated with cooling towers, evaporative condensers, and other water supplies found with air-conditioning units of buildings. Infectious aerosols may be generated from these units, allowing for a respiratory route of infection. Though the disease is thus spread in an airborne manner, there is no evidence that it can be passed from person to person.

The epidemiological evidence for the disease supports an airborne hypothesis. Most outbreaks have occurred in regions of soil disruption, such as that occurring during construction. Subsequent isolation of Legionella bacteria from the cooling towers confirmed such contamination. Though the air-conditioning unit of the Bellevue-Stratford Hotel in Philadelphia was replaced prior to isolation of the organism, the assumption is that the unit was contaminated. The outbreaks of the disease during the summer, when air-conditioning use has peaked, are consistent with the role of air-conditioning units in the spread of Legionella bacteria.

The method by which the Legionella bacterium survives in the environment has not been completely determined. The organism is somewhat resistant both to chlorine treatment and to heat as high as 65 degrees Celsius. It appears to grow best in the presence of biological factors secreted by other microflora in the environment; growth stimulation may also be enhanced by the presence of physical factors such as sediment, silicone, and rubber compounds. Its ability to survive, and indeed be transmitted, may also be related to its tendency to penetrate and multiply intracellularly within environmental protozoa or amoeba.

Prevention of disease transmission must take into account these problems. Contamination of water supplies must be minimized. The resistance of the Legionella bacterium to standard methods of decontamination has made the process more difficult, and methods of choice remain controversial. Chlorination at relatively high levels remains the preferred method, with subsequent treatment at lower concentrations over the long term. The disadvantages of this method include the cost of constant treatment and the eventual corrosion of the units. Continuous or intermittent heating of the water has also proved effective in decontamination.

Perspective and Prospects

Prior to August 1976, Legionnaires’ disease was unknown. From July 21 to 24 of that year, however, the Pennsylvania branch of the American Legion held its annual convention at the Bellevue-Stratford Hotel in Philadelphia. Some four thousand delegates and their families attended the festivities. Following the convention, as delegates returned to their homes, a mysterious illness began to appear among the attendees. A total of 149 conventioneers and 72 others became ill. Characterized by a severe respiratory infection that progressed into pneumonia, and high fever, the illness proved fatal to thirty-four of the victims.

By August, it became clear to the Pennsylvania Department of Health that an epidemic was at hand. The cause of the outbreak was not clear, and rumors began to circulate. At various times, the news media explained the outbreak as a Communist plot against former military men, a Central Intelligence Agency test gone awry, and even an infectious agent arriving from space. The truth was less dramatic. By the beginning of 1977, David Fraser, Joseph McDade, and their colleagues from the Centers for Disease Control isolated the etiological agent: a bacterium subsequently named Legionella pneumophila.

With the isolation and identification of the organism, it became possible to explain earlier outbreaks of unusual illness. For example, during July and August of 1965, an outbreak of pneumonia at a chronic-care facility at St. Elizabeth’s Hospital in Washington, D.C., resulted in eighty-one cases and fourteen deaths. An outbreak among personnel at the Oakland County Health Department in Pontiac, Michigan, during July and August of 1968 of a disease that was subsequently called Pontiac fever was also traced to the same organism. In this case, however, though 144 persons were affected, none died. In fact, illness associated with the Legionella bacterium has been traced as far back as 1947. The 1976 outbreak was not new; it was merely the first time that medical personnel were able to isolate the organism that caused the disease.

The precise prevalence of the Legionella bacterium remains murky, but it is clearly more common than was at first realized. In 2013, the Centers for Disease Control and Prevention reported that between eight thousand and eighteen thousand people with the disease are hospitalized annually in the United States. These figures do not include cases that are undetected or unreported, however, so the actual number of cases might be much higher.

Despite the public’s fear of the disease, in most instances it probably remains a mild respiratory infection, resembling nothing worse than a bad cold. Most cases remain undetected. A study of hospitalized community-acquired pneumonia patients conducted in Ohio showed that about 3 percent of cases were caused by Legionella. Estimates have suggested that as many as twenty-five thousand persons in the United States develop infection. Based on seroconversions—the production of anti-Legionella antibody in the sera of persons—it has been estimated that more than 20 percent of the population of Michigan has been exposed to the organism. There is no reason to doubt that the same situation exists in many other states.

In addition to sporadic cases, outbreaks continue to occur around the world. In Toronto in 2005, a colonized air-conditioning cooling tower atop the Seven Oaks Home for the Aged caused illness in 127 residents and workers, and 20 of the residents died. Similarly, a strain of Legionella was traced back to a cooling tower in an office building in Quebec that had led to 180 cases and thirteen deaths in 2013. As for the United States, an increased number of outbreaks occurred in New York, Illinois, and California in the summer of 2015. Officials in New York City eventually located the source of the strain in a cooling tower on top of the Opera House Hotel after twelve people died and more than 120 people were afflicted with the disease. The other two outbreaks included several confirmed cases involving people living in the Illinois Veterans' Home in Quincy, Illinois, and prisoners at the San Quentin State Prison north of San Francisco. As of late August, four people had died in Illinois.

The basis for the difference in severity between Legionnaires’ disease and Pontiac fever is also unclear. There is no obvious difference between the two diseases that accounts for the differences in virulence. It also remains to be seen whether Legionella bacteria are associated with other illnesses.

The final lesson of Legionnaires’ disease is as subtle as its initial appearance. Humans exist in an environment replete with infectious agents. Despite the battery of modern methods of treatment for illness, there always remains the potential for new outbreaks of previously unknown disease.

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